Human herpes virus 8 (HHV8), also known as Kaposi's sarcoma associated herpes virus (KSHV) is the most frequent cause of malignancy among AIDS patients. Infection with HHV8 has been linked to the occurrence of Kaposi's sarcoma (KS) and several lymphoproliferative disorders, such as primary effusion lymphoma (PEL) and multicentric Castleman's disease. However, the exact mechanism of action of HHV8 in the pathogenesis of these disorders is still unclear. We have discovered that K13, an HHV8-encoded vFLIP (viral FLICE inhibitory protein), possesses the unique abilities to activate the classical and alternative NF-?B pathways by interacting with different components of the I?B kinase (IKK) complex. We have further demonstrated that K13 is an oncogene which mediates increased cellular proliferation, transformation, cytokine secretion and protection against growth factor withdrawal-induced apoptosis via NF-?B activation. The overall goal of this proposal is to further understand the mechanism of NF-?B activation by K13 and identify the downstream genes involved in its various biological activities. We plan to achieve this goal through the following specific aims. In aim 1, we will characterize the molecular interactions of K13 involved in classical and alternative NF-?B activation. In aim 2, we will characterize the role of post-translational modifications and nuclear functions of the IKK complex subunits in K13-induced classical and alternative NF-?B pathways. Aim 3 will focus on identifying the downstream targets of K13-induced classical and alternative NF-?B pathway. Finally, aim 4 will study the contribution of the classical and alternative NF-?B pathways in K13-induced cellular transformation and protection against growth-factor-withdrawal-induced apoptosis. We hope that these studies will lead to the identification of genes and proteins that are critically involved in the pathogenesis HHV8-associated diseases and, therefore, are ideal candidates for the development of molecularly targeted therapies. [unreadable] [unreadable]